Central apnea and dysrhythmia is typical for sleep apnea and Rett Syndrome patients as well as Sudden Infant Death Syndrome victims. Since respiratory pacemakers are likely to underlie respiratory rhythmogenesis (Pena et al. 2004), investigating their properties is critical to understanding how the rhythm is generated and maintained. In order for pacemakers to burst repetitively, their membrane potential (Vm) must be maintained within a range where bi-stable properties are expressed. Outside this range, pacemakers are typically either tonically active or silent. For rhythmic pacemaker bursting activity to be stable and regular, the membrane potential must be maintained at a sufficiently depolarized level to reliably trigger bursting at regular periods. We will examine whether background sodium currents (BSC) determine the regularity of respiratory pacemaker bursting and network rhythmic behavior. Irregular respiratory network and pacemaker bursting may result in irregular breathing periods underlying respiratory diseases such as;Rett Syndrome. Substance P and 5HT2A receptor modulation are proposed to be essential to the generation of regular breathing patterns. Along these lines, we showed Substance P can restore regular respiratory activity to otherwise irregular respiratory network activity generated by MECP2-/-, which share the same mutation and breathing irregularities as Rett children. Mechanistically, Substance P modulates a BSC and enhances regularity of respiratory pacemakers, that in turn is proposed to enhance regular respiratory activity. Another BSC modulator, 5HT2A, is essential for regular fictive eupneic and gasping activity, the deficit of which may underlie irregular gasping and failure to autoresuscitate in SIDS victims. We will examine which components of the BSC (persistent versus sodium leak current) that Substance P and 5HT modulate to alter pacemaker bursting regularity. This research will lead to better understanding of the ionic mechanisms behind the generation of regular versus irregular rhythmic respiratory activity.